Alzheimer?s disease (AD) is a fatal neurodegenerative disorder that affects one in 10 individuals over 65 andnearlyhalfofthoseover85.Thenumberofpeopleaffectedbythisdiseaseandthecorrespondingcostto society is predicted to double within 20 years. To develop effective therapies, new biomedical approaches, concepts,andmoleculartargetsarecriticallyneeded. The discovery of novel classes of molecules called non-protein-coding RNA (ncRNA) has revolutionized biology and is predicted to have a major impact on medicine. Among them are microRNAs (miRNA), small post-transcriptional regulators of gene expression, and long ncRNAs (lncRNA) that operate via diverse molecular mechanisms, the classes implicated in various physiological and pathological conditions. Accumulating evidence suggests that dysregulation of both miRNA and lncRNA may play important roles in neurodegenerative diseases, including in AD. For example, a specific miRNA, miR-132, previously implicated in neuronal development, plasticity, and viability, has recently emerged as the most significantly down- regulatedinearlystagesofADandassociatedwiththeADpathology,includingbothamyloidplaquesandtau- formed neurofibrillary tangles. Our data indicate that miR-132 protects neurons against disease-related toxins such as Abeta and glutamate. On the other hand, several lncRNAs with unknown functions appear significantly elevated in AD, and we hypothesize their role in tethering the key neuronal miRNAs such as miR-132. We propose, therefore, that miRNA and lncRNA form regulatory networks controlling gene expression in cortical neurons,andthatdysregulationofthesemiRNA-lncRNAnetworksmaycontributetoADpathogenesis.Totest our hypothesis, and investigate neuronal functions of top AD-associated lncRNAs (?AD-lncRs?), we propose twoSpecificAims. SpecificAim1willrevealthecompletemiRNAinteractomeinhumanneuronsanditsalterationsinaging and in the context of disease-causing mutations. Using a combination of functional assays and RNA cross- linking techniques, we will define physiologically important miRNA binding partners, with the focus on both mRNAandlncRNA.SpecificAim2willinvestigatethefunctionsofAD-lncRsandtheirfunctionalrelationships with the key neuronal miRNAs. Using a combination of gain-of-function and loss-of-function approaches to modulate AD-lncRs in human neurons, we will examine their effects on miRNA activity and neuronal health. The proposed project promises to yield significant new insights into the regulation of gene expression in AD andmaysuggestlncRNAsasanovelclassofmoleculartargetsforADtherapy.